Inhibitory receptors on lymphocytes: insights from infections

Abstract

Costimulatory and inhibitory receptors are critical regulators of adaptive immune cell function. These pathways regulate the initiation and termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. This review focuses on recent advances in our understanding of inhibitory receptor pathways and their roles in different diseases and/or infections, emphasizing potential clinical applications and important unanswered mechanistic questions. Although significant progress has been made in defining the influence of inhibitory receptors at the cellular level, relatively little is known about the underlying molecular pathways. We discuss our current understanding of the molecular mechanisms for key inhibitory receptor pathways, highlight major gaps in knowledge, and explore current and future clinical applications.

Figure 1. Major Inhibitory Receptor Mechanisms of Action

Mechanism #1: Inhibitory receptors prevent T cells (or B cells) from receiving complete activation signals by sequestering the ligands for co-stimulatory receptors. Mechanism #2: Inhibitory sequence motifs, such as ITIMs or ITSMs, on the cytoplasmic tail of inhibitory receptors are phosphorylated upon cellular activation. These motifs then recruit intracellular phosphatases that dephosphorylate signaling molecules downstream of the TCR (or BCR) and co-stimulatory molecules, causing a broad, quantitative reduction in activation-induced gene expression. Mechanism #3: Inhibitory receptors have recently been demonstrated to upregulate genes that inhibit immune cell function; however, the pathways leading to this gene upregulation are not known.